title: COMT Val158Met genotype selectively alters prefrontal [18F]fallypride displacement and subjective feelings of stress in response to a psychosocial stress challenge.
abstract: Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val(158)Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [(18)F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [(18)F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [(18)F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed.
authors.affiliation: Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, School for Mental Health and NeuroScience MHeNS Maastricht University, Maastricht, The Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Hernaus
authors.forename: Dina
authors.initials: D
authors.lastname: Collip
authors.forename: Johan
authors.initials: J
authors.lastname: Lataster
authors.forename: Jenny
authors.initials: J
authors.lastname: Ceccarini
authors.forename: Gunther
authors.initials: G
authors.lastname: Kenis
authors.forename: Linda
authors.initials: L
authors.lastname: Booij
authors.forename: Jens
authors.initials: J
authors.lastname: Pruessner
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.forename: Ruud
authors.initials: R
authors.lastname: van Winkel
authors.forename: Jim
authors.initials: J
authors.lastname: van Os
authors.forename: Inez
authors.initials: I
authors.lastname: Myin-Germeys
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001549:Benzamides / Q000493:pharmacokinetics*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000201:enzymology*; D011618:Psychotic Disorders / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics* / Q000523:psychology; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D013315:Stress, Psychological / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics* / Q000523:psychology; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D001549:Benzamides; C094948:N-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2,3-dimethoxybenzamide; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D002394:Catechol O-Methyltransferase